Glucagon has been shown to be a diabetogenic hormone, particularly in states of insulin deficiency. Thus, understanding mechanisms which may decrease glucagon activity in the organism may provide useful approaches in the management of diabetes. Recent observations have focused upon the role of receptors in hormone action. In addition, receptor diseases have been uncovered as in Graves disease, myasthenia gravis, insulin-resistant diabetes and LDL receptor defects in Type II hyperlipidemia. We propose to study the factors and mechanisms involved in regulation of the glucagon receptor in normal and diabetic states. We have already shown that diabetes and elevated levels of plasma glucagon (IRG) decrease hepatic glucagon receptors. However, the specific influence of factors such as hyperglycemia, insulin-lack, etc., remains to be classified. We postulate that of the heterogeneous species of plasma IRG, only the 3500 d. moiety may be capable of down-regulating receptors, and certain of the others may be involved in blocking glucagon receptors. Circulating mononuclear cells are the only readily available source for receptor defect studies in humans. We will first determine whether the changes occurring in liver glucagon receptors are reflected in monocytes. Then glucagon binding will be studied in monocytes of various subjects. Though no disease involving glucagon receptor dysfunction has yet been described, it is possible that glucagon receptor dysfunction may be an underlying primary mechanism for certain kinds of hypoglycemia and may be secondarily involved in other states such as uremia, cirrhosis and diabetes.